Mononuclear phagocytes regulate inflammatory and immunological responses and are a critical cell type in the pathogenesis of chronic diseases such as rheumatoid arthritis. Potentially detrimental effects of uncontrolled monocyte activation are normally prevented by monocyte deactivating factors such as TGFbeta, IL-4 and IL-10. A large amount of information is available that documents activation of the mononuclear phagocyte system in RA blood, synovial fluid and tissue. We propose the hypothesis that defects in monocyte deactivation may contribute to chronic synovial inflammation in RA. This could be due to genetic defects or the result of changes that occur as part of the disease process. In this proposal we will also define basic mechanisms by which deactivating factors such as IL-10 or TGFbeta inhibit monocyte function and this part of the application is based on the hypothesis that inhibition of protein tyrosine kinase activation provides a potent mechanism of monocyte deactivation which may be utilized by monocyte deactivation factors. Specifically, we will (i) define the effects of deactivation factors on cell surface receptors for monocyte activators and on DNA binding proteins that are known to be involved with monocyte activation (ii) characterize effects of monocyte activators and deactivators on specific protein kinases (iii) analyze levels of monocyte deactivation factors in rheumatoid arthritis peripheral blood, synovial fluid and synovial tissue (iv) determine the responsiveness of rheumatoid arthritis monocytes to the deactivation factors IL-10, TGFbeta and IL-4. Identification of defects in monocyte deactivation in RA and characterization of the principal intracellular events during monocyte deactivation will define novel targets for therapeutic interventions to inhibit the proinflammatory and tissue destructive activation of monocytes in the rheumatoid joint.